Env-specific IgG markedly enhances HIV-1 and SIV transcytosis across genital and gut epithelial cells in vitro. The enhanced transcytosis is mediated by the Fc neonatal receptor (FcRn), which binds lgG-containing immune complexes (ICs) at low pH, shuttles them through epithelial cells, and releases them at neutral pH. We found that with four different vaccine regimens, FcRn-mediated transcytosis activity in serum of vaccinated macaques strongly correlated with the number of T/F variants infecting the animals after repeated low-dose SIVmac251 rectal challenges. Moreover, with ALVAC-based vaccine regimens that provided up to 40% protection, animals with high vaccine-induced serum FcRn-mediated transcytosis activity became infected with fewer challenges than those with low activity, and animals that remained uninfected always had very low activity. Thus, vaccines simultaneously protected some animals while driving infection and more T/F strains in others. We address this conundrum and so seek to understand relationships between beneficial and deleterious antibodies by testing the following hypothesis: 1) relative levels of vaccine-induced antiviral and enhancing antibodies are key determinants of T/F variant selection and infection acquisition. We will also explore why, mechanistically, FcRn-mediated transcytosis so strongly impacts infection. FcRn only binds well to IgG or ICs at low pH (=~6.5), and our preliminary data indicate that macaque rectal secretions are infrequently acidic. However, Fc? receptors (Fc?Rs), which bind ICs at neutral pH, are expressed along with FcRn in macaque rectal epithelial cells. In view of these and other observations, we propose a novel hypothesis: 2) infectious ICs enter rectal epithelial cells via Fc?Rs at the usually pH-neutral rectal mucosa, followed by FcRn-dependent delivery to subepithelial tissue where infection occurs. To test these hypotheses we will accomplish the following: Specific Aim 1. Delineate relationships between antiviral antibodies, enhancing antibodies, T/F strain selection, and infection outcome following ALVAC-SIV/gp120 vaccination. We will measure the breadth and potency of vaccine-induced neutralizing, ADCC, virus-capturing, and FcRn-mediated enhancing antibodies in serum and rectal IgG against a panel of T/F strains that established infection after repeated low dose SIVmac251 rectal challenge. We will also model T/F selection in vitro with a novel approach. Specific Aim 2. Determine the mechanisms underlying the association between FcRn-mediated transcytosis and infection outcomes. Using engineered cells and rectal tissue explants, we will determine if SIV- or HIV-1-ICs are internalized via Fc?Rs prior to FcRn-dependent shuttling across the epithelium. We have uncovered a unique antibody activity that is strongly associated with infection outcome following vaccination. Defining the implications and mechanisms of this activity could lead to new insights into how opposing antibody functions interact with each other, to novel targets for microbicides, and to vaccine strategies that elicit maximal antiviral responses with minimal deleterious effects.